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Cnidaria small cysteine-rich proteins (SCRiPs) were the first family of neurotoxins detected in stony corals, one of the ocean\u2019s most crucial foundation species. Yet, their molecular evolution remains poorly understood. Moreover, the lack of a clear classification system has hindered the establishment of an accurate and phylogenetically informed nomenclature. In this study, we extensively surveyed 117 genomes and 103 transcriptomes of cnidarians to identify orthologous SCRiP gene sequences. We annotated a total of 168 novel putative SCRiPs from over 36 species of stony corals and 12 species of sea anemones. Phylogenetic reconstruction identified four distinct SCRiP subfamilies, according to strict discrimination criteria based on well-supported monophyly with a high percentage of nucleotide and amino acids\u2019 identity. Although there is a high prevalence of purifying selection for most SCRiP subfamilies, with few positively selected sites detected, a subset of Acroporidae sequences is influenced by diversifying positive selection, suggesting potential neofunctionalizations related to the fine-tuning of toxin potency. We propose a new nomenclature classification system relying on the phylogenetic distribution and evolution of SCRiPs across Anthozoa, which will further assist future proteomic and functional research efforts.<\/jats:p>","DOI":"10.3390\/toxins16020075","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T09:42:32Z","timestamp":1706866952000},"page":"75","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Evolutionary Analysis of Cnidaria Small Cysteine-Rich Proteins (SCRiPs), an Enigmatic Neurotoxin Family from Stony Corals and Sea Anemones (Anthozoa: Hexacorallia)"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5277-3940","authenticated-orcid":false,"given":"Ricardo Alexandre","family":"Barroso","sequence":"first","affiliation":[{"name":"CIIMAR\/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos, s\/n, 4450-208 Porto, Portugal"},{"name":"Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9617-2741","authenticated-orcid":false,"given":"Luana","family":"Ramos","sequence":"additional","affiliation":[{"name":"CIIMAR\/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos, s\/n, 4450-208 Porto, Portugal"},{"name":"Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0792-5968","authenticated-orcid":false,"given":"Hugo","family":"Moreno","sequence":"additional","affiliation":[{"name":"CIIMAR\/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos, s\/n, 4450-208 Porto, Portugal"},{"name":"Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1328-1732","authenticated-orcid":false,"given":"Agostinho","family":"Antunes","sequence":"additional","affiliation":[{"name":"CIIMAR\/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos, s\/n, 4450-208 Porto, Portugal"},{"name":"Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13227-020-00171-w","article-title":"Insights into how development and life-history dynamics shape the evolution of venom","volume":"12","author":"Surm","year":"2021","journal-title":"Evodevo"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Schendel, V., Rash, L.D., Jenner, R.A., and Undheim, E.A.B. (2019). The Diversity of Venom: The Importance of Behavior and Venom System Morphology in Understanding Its Ecology and Evolution. 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